This application is in response to RFA-NS-13-003, NIH Blueprint for Neuroscience Research Grand Challenge: Discovering Novel Drugs for Disorders of the Nervous System (U01). Orexin- A (OXA) and orexin-B (OXB), also known as hypocretin-1 and hypocretin-2, are lateral hypothalamic (LH) neuropeptides that stimulate orexin-1 (OX1) and orexin-2 (OX2) receptors. Recently, our laboratory and others have generated compelling evidence that OXA peptide, acting through OX1 receptors, regulates the stimulatory effects of nicotine on brain reward systems and thereby controls nicotine self-administration behavior in rats and mice. In addition, OX1 receptors regulate the relapse-like reinstatement of extinguished drug-seeking responses in abstinent rats and mice. Indeed, the development of OX1 receptor antagonists that are safe for use in humans is considered perhaps the most promising approach to developing novel therapeutic agents for tobacco dependence and other substance abuse disorders in humans. We aim to facilitate the design, synthesis and testing in relevant preclinical models, of novel OX1 receptor antagonists through the Blueprint Neurotherapeutics Network. We have identified novel chemical scaffolds that are yielding selective OX1 receptor antagonists that should be suitable for development through the Blueprint Network. We have developed robust cell-based assays to reliably OX1 receptor antagonist actions (and appropriate counterscreens). In addition, we have established the most relevant animal model of nicotine addiction currently available, the intravenous nicotine self-administration procedure, in mice. We can now assess the effects of novel OX1 receptor antagonists on nicotine reinforcement in wildtype mice to determine if the compounds demonstrate in vivo efficacy. Also, the effects of novel OX1 receptor antagonists on responding for nicotine in OX1 receptor knockout mice can be assessed, thereby determining if the compounds are behaviorally selective. This exciting drug development program capitalizes on the unique capabilities of Blueprint Neurotherapeutics Network. It will leverage our progress to date in identifying novel chemical scaffolds and take advantage of our highly relevant in vitro and in vivo assays. Hence, this program promises to yield OX1 receptor antagonists as novel therapeutic for smoking cessation.